Fortilin, p53, and atherosclerosis

Fortilin、p53 和动脉粥样硬化

• 批准号: 8431876
• 负责人: Ken Fujise
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431876
• 关键词: 3-Dimensional; Acute myocardial infarction; Amino Acids; Apoptosis; Apoptotic; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Cell Line; Cell physiology; Cells; Cessation of life; Cholesterol; Coronary Arteriosclerosis; Cytokine Signaling; Cytosol; DNA Fragmentation; Death Rate; Disease; Encapsulated; Enzyme-Linked Immunosorbent Assay; Exhibits; Figs - dietary; Flow Cytometry; Foam Cells; Foundations; Genes; Genetic; Glucans; Goals; Human; Hydroxymethylglutaryl-CoA reductase; Infection; Infiltration; Inflammation; Inflammatory; Intention; Knockout Mice; Laboratories; Low-Density Lipoproteins; Luciferases; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Molecular Target; Mus; Mutate; Nature; Neoplasms; Noxae; Nuclear; Oral; Outcome; Pathway interactions; Patients; Play; Production; Proliferating; Proteins; Reagent; Regulation; Reporting; Research; Role; Serum; Small Interfering RNA; System; TP53 gene; TPT1 gene; Techniques; Testing; Time; Trauma; Tumor Suppressor Proteins; United States National Institutes of Health; base; bench to bedside; combat; cost; cytokine; improved; macrophage; monocyte; mortality; novel; overexpression; particle; prevent; public health relevance; small molecule

DESCRIPTION (provided by applicant): The overall goal of this grant proposal entitled "Fortilin, p53, and atherosclerosis" is to define a novel role of fortilin and the fortilin-p53 interaction in atherosclerosis with the intention of establishing anti- fortilin therapy as a viabl strategy against atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection, and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied fortilin, a 172-amino acid multi-functional protein for the last 15 years. In 2001, we reported for the first time that fortilin protects cells against apoptosis. More recently, we showed that fortilin mediates its anti apoptotic activity through its binding to and inhibition of p53, a tumor suppressor protein. Since (a) p53 protects against not only cancer but also atherosclerosis and (b) fortilin blocks p53, we tested whether the lack of fortilin ameliorated atherosclerosis using Ldlr-/-Apobec1-/- hypercholesterolemic mice, a robust model of atherosclerosis. Strikingly, fortilin+/+Ldlr-/-Apobec1-/- mice had 27 % more atherosclerosis than fortilin+/-Ldlr-/-Apobec1-/- mice with extensive macrophage (M¿) infiltration in the atheroma. In addition, immunostaining showed that fortilin is overexpressed in M¿ and foam cells within human and mouse atherosclerotic lesions. Further, monocytes from patients with coronary atherosclerosis have higher fortilin levels. Finally, we found that hypercholesterolemic sera induce fortilin in M¿. Based on these facts, we hypothesize that (a) pro-atherosclerotic milieu induces fortilin in M¿, (b) M¿-fortilin, when induced, protects M¿ against p53-induced apoptosis, and (c) unchecked M¿ proliferate and produce pro- inflammatory cytokines creating a vicious cycle of inflammation and atherosclerogenesis. The facilitative role of M¿-fortilin through p53 has never been postulated or tested. To test this overall hypothesis, we propose four Specific Aims. In Aim 1, we investigate how fortilin is induced in M¿ and what role induced fortilin plays in M¿, using primary and cell line M¿. In Aim 2, we first define the molecular mechanism by which M-fortilin promotes atherosclerogenesis, using M¿-specific fortilin knockout (KO) mice on the Ldlr-/- Apobec1-/- genetic background (Aim 2.1.). Next, we examine whether fortilin facilitates atherosclerosis through its inhibition of p53, by creating M¿-specific fortilin KO mice on the p53-/-Ldlr-/-Apobec1-/- genetic background (Aim 2.2.). In Aim 3, we expect to show that M¿-specific fortilin silencing re-activates p53 and protects against atherosclerosis by orally administering ¿1,3-D-glucan-encapsulated (GeRP) fortilin siRNA particles to Ldlr-/- Apobec1-/- mice. At the end of the project, we expect M¿-specific anti-fortilin therapy to be found to be a ground-breaking strategy against the deadly and global disease of atherosclerosis.

描述（由适用提供）：该赠款提案的总体目标标题为“ Fortilin，p53和动脉粥样硬化”是为了确定Fortilin和Fortilin-P53相互作用在动脉粥样硬化中的新作用，目的是建立抗多胺疗法作为针对动脉粥样硬化的抗毛素治疗。到2025年，由于动脉粥样硬化和相关并发症而导致的全球死亡预计将超过每种主要疾病，包括癌症，感染和创伤。仅美国，与动脉粥样硬化有关的疾病的总成本估计为2860亿美元。他汀类药物之后，管道中没有打击这种致命的全球疾病的策略。我们的实验室拥有Studiod Fortilin，这是过去15年来的172个氨基酸多功能蛋白。 2001年，我们首次报道了ForiTILIN保护细胞免受凋亡的影响。最近，我们证明了Foritilin介导了其抗 凋亡活性通过其与肿瘤抑制蛋白p53的结合和抑制作用。由于（a）p53不仅可以防止癌症，还可以防止动脉粥样硬化和（b）Fortilin阻滞p53，因此我们测试了缺乏使用LDLR - / - apobec1 - / - 高胆固醇血症小鼠，一种强大的动脉粥样硬化模型来改善动脉粥样硬化。引人注目的是，与Fortialin +/- ldlr - / - Apobec1 - / - 小鼠相比，Fortilin+/+LDLR - / - APOBEC1 - / - 小鼠的动脉粥样硬化多27％。此外，免疫染色表明，在人和小鼠动脉粥样硬化病变中的M泡中，Fortirin在M os中过表达。此外，来自冠状动脉粥样硬化患者的单核细胞具有较高的前林水平。最后，我们发现高胆固醇血清诱导了M？。基于这些事实，我们假设（a）促进性环境对M？的影响，（b）m fortilin诱导时，可以防止M frove p53诱导的凋亡，并且（c）未经检查的M€增殖并产生促炎的细胞，从而产生了精彩的炎症和炎症周期。通过p53通过p53的促进作用从未被假定或测试。为了检验这一总体假设，我们提出了四个具体目标。在AIM 1中，我们研究了使用原代和细胞系M诱导的M诱导的Fortilin在M诱导的M诱导的作用。在AIM 2中，我们首先使用M-特定于LDLR - / - APOBEC1 - / - 遗传背景（AIM 2.1。）在LDLR - / - APOBEC1-/ - 遗传背景上使用M€特异性的Fortilin敲除（KO）小鼠来促进动脉粥样硬化的分子机制。接下来，我们通过在p53 - / - ldlr - / - apobec1-/ - 遗传背景（AIM 2.2。）上创建M€特异性的Fortialin KO小鼠（AIM 2.2。），通过创建M€特异性的Fortilin KO小鼠来检查ForiTILIN最受欢迎的动脉粥样硬化。在AIM 3中，我们期望表明，特异性的前林沉默会重新激活p53，并通过口服口服»1,3-d-d-glucan封装（GERP）FORITILIN siRNA颗粒来预防动脉粥样硬化。在该项目结束时，我们预计发现，特定的抗波纹细菌疗法是针对动脉粥样硬化致命和全球疾病的开创性策略。